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Association of Promoter Variants in the 7 Nicotinic Acetylcholine Receptor Subunit Gene With an Inhibitory Deficit Found in Schizophrenia

Sherry Leonard, PhD; Judith Gault, PhD; Jan Hopkins, BS; Judith Logel, MS; Ruby Vianzon, BS; Margaret Short, BS; Carla Drebing, BS; Ralph Berger, BS; Diana Venn; Pinkhas Sirota, MD; Gary Zerbe, PhD; Ann Olincy, MD; Randal G Ross, MD; Lawrence E. Adler, MD; Robert Freedman, MD

Arch Gen Psychiatry. 2002;59:1085-1096.

Background  The 7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects.

Methods  Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded.

Results  Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an 7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response.

Conclusions  Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.

From the Departments of Psychiatry (Drs Leonard, Gault, Olincy, Ross, Adler, and Freedman; Mss Logel, Vianzon, Drebing, and Venn; and Mr Berger), Pharmacology (Drs Leonard and Freedman), and Preventive Medicine and Biometrics (Dr Zerbe), University of Colorado Health Sciences Center, and the Denver Veterans Affairs Medical Center (Drs Leonard, Olincy, Ross, Adler, and Freedman and Mss Hopkins and Short), Denver; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Dr Sirota).

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